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RIFAMPIN EFFECT ON TENOFOVIR ALAFENAMIDE (TAF) PLASMA/INTRACELLULAR PHARMACOKINETICS
Maddalena Cerrone1, Omamah Alfarisi2, Megan Neary3, Mark A. Marzinke2, Teresa Parsons2, Andrew Owen3, Gary Maartens4, Anton Pozniak1, Charles W. Flexner2, Marta Boffito1
1Chelsea and Westminster Hospital, London, UK,2The Johns Hopkins University, Baltimore, MD, USA,3University of Liverpool, Liverpool, UK,4University of Cape Town, Cape Town, South Africa
TAF produces lower plasma and higher intracellular (IC) tenofovir (TFV) concentrations than tenofovir disoproxil fumarate (TDF), but is a substrate of drug transporters (e.g. BCRP; ABCG2; ABCB1) and therefore a potential victim of drug interactions, especially with inducers like rifampin (RIF) that act via nuclear receptors such as PXR (NR1I2) and CAR (NR1I3).
This study is the first to measure the pharmacokinetics (PK) of TAF once-daily (OD) with RIF and compare it directly to TDF. Healthy volunteers aged 18-65 years received TAF/ FTC 25/200mg OD (28 days) with food, followed by TAF/FTC+RIF 600mg OD (28 days, RIF on empty stomach followed by TAF/FTC with meal after 30 mins), followed by TDF 300mg OD (28 days) with food. Intensive PK sampling occurred on days 28 (TAF/FTC), 56 (TAF/FTC+RIF) and 84 (TDF), and plasma TAF, TFV, FTC and IC TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) concentrations were measured by validated LC-MS methods. Subjects were genotyped for polymorphisms in NR1I2 (rs2472677), NR1I3 (rs2307424), CYP3A4 (rs35599367), and ABCG2 (rs2231142).
17 subjects completed all PK phases (14 females). Plasma TAF and TFV geometric mean ratios (GMR, TAF+RIF vs TAF) and 90% confidence intervals (CI) for the main PK parameters calculated are illustrated in the Table, as well as IC TFV-DP GMR (90%CI). Mean TFV-DP AUC was 122,920 on PK2 versus 24,247 h*fmol/million-cells on PK3. Plasma TFV/IC TFV-DP AUC ratio was unchanged by RIF co-administration (0.001), suggesting that RIF mainly affects TAF absorption and not clearance. FTC-TP PK parameters were not affected by RIF. All polymorphisms were in Hardy-Weinberg equilibrium, and no consistent associations were observed after correction for multiple comparisons.
Relative to TAF 25mg OD, following administration of TAF OD with RIF, plasma TAF Cmax and AUC were decreased by 45% and 47%, respectively, while IC TFV-DP concentrations were decreased by 40%. However, IC TFV-DP concentrations were still 82% higher on average than those achieved by standard dose TDF. These data support further study of TAF when co-administered with RIF in patients with HIV and tuberculosis.